U.S. Pat. No. 4,017,513 describes resin-mediated (i.e., Dowex 50WX8 cation-exchange resin) synthesis of optically pure amino acid amides. These resin-based methods for amino acid amide synthesis comprise (a) esterification of an amino acid with methanol and (b) reaction of the ester with ammonia to form the amide (FIG. 1). Most amino acids are unreactive in polar solvents such as methanol because of zwitterion formation, but amino acid adsorption on a cation-exchange resin with, e.g., sulfonic acid groups, activates the amino acid molecules to esterification and subsequent amidation.
In the esterification reaction, the ion-exchange resin does not act as a catalyst because the ester remains adsorbed to the resin. Consequently, stoichiometric amounts of acid sites are required for complete amino acid esterification.
The process described in U.S. Pat. No. 4,017,513 is carried out in vessel containing an agitated slurry of resin particles with which the reactants are admixed. Ammonia is introduced as a vapor into the headspace of the reaction vessel, and is absorbed into the reaction slurry. Considerable resin attrition occurs in such a process due to the high agitation rates that are required to suspend the resin and contact it thoroughly with the reactants. Such agitation results in mechanical degradation of resin, i.e., the production of fine resin particles. The fine resin particles slow processing significantly because filtration of slurries containing fine solids is very slow. Further, fine particles are likely to increase the surface tension of the slurry and decrease the rate of ammonia absorption into the slurry, resulting in a slow amidation reaction. Thus, when practicing a process that requires filtration, either of final product or of some reaction intermediate, the production of fine particles should be avoided. Suspension of large amounts of dense resin particles with minimal attrition is particularly difficult in pilot-plant or production-scale reaction vessels. Thus, there is a need in the art for methods for the synthesis of amino acid amides using cation exchange resins which do not suffer from the problems associated with fine particle formation due to agitation of resin.